1. Technical Field
The present invention is directed to oligonucleotide duplex compounds which have anticancer activity. The present invention is also directed toward certain modified oligonucleotide compounds which are capable of self-forming a duplex structure, and which have anticancer activity.
2. Brief Description of Background Art
Oligonucleotides have been intensely studied in the prior art as potential chemotherapeutic agents. Methods have been developed for synthesizing oligonucleotides which include the major naturally occurring nucleosides, as well as nucleosides containing modified heterocyclic bases. Methods have also been developed for the synthesis of oligonucleotides which contain modified sugars, as well as modifications in the "phosphate backbone" of the nucleotidic chain. Oligonucleotides containing 2'-O-methyl ribose, arabinose and particularly .alpha.-arabinose (U.S. Pat. No. 5,177,196) as well as phosphorothioate linkages serve as examples. Oligonucleotides having various "tails" covalently attached to either their 3'- or to their 5'-ends, or to both, have also been known in the art. Generally speaking, intercalating groups, various kinds of reporter groups and lipophilic groups have been attached to the 3' or 5' ends of the oligonucleotides. Attachment of linking groups to the 3'-end of oligonucleotides, which in turn are attached to an intercalating group, reporter group or lipophilic group, have been described in the prior art. The group derived from the linking group amino-2,3-propane diol serves as an example. A method of synthesizing oligonucleotides on a solid phase support, using optically pure 2-(hydroxymethyl)-4-hydroxy-pyrrolidine as a group which links the growing oligonucleotide chain to the solid support as well as to a desired "tail moiety", such as a lipophilic moiety, is described in a patent application having one or more inventors in common with the present application. Descriptions of syntheses of 3'-cholesterol or 3'-acridine modified oligonucleotides can be found in the articles: Gamper, H. B., Reed, M. W., Cox, T., Virosco, J. S., Adams, A. D., Gall, A., Scholler, J. K., and Meyer, R. B. (1993) Facile Preparation and Exonuclease Stability of 3'-Modified Oligodeoxynucleotides. Nucleic Acids Res. 21 145-150; and Reed, M. W., Adams, A. D., Nelson, J. S., and Meyer, R. B.,Jr. (1991) Acridine and Cholesterol-Derivatized Solid Supports for Improved Synthesis of 3'-Modified Oligonucleotides. Bioconjugate Chem. 2 217-225 (1993).
As far as potential chemotherapeutic agents, the so-called "antisense" oligonucleotides have been the focus of the most intense research, since such compounds, if designed to be complementary to a target RNA sequence, promise the ability to hybridize with messenger RNA, and therefore interfere with the synthesis of distinct proteins within the cell. To this date however, results with antisense oligonucleotides (ODNs) have been somewhat disappointing in terms of successful chemotherapy. Nevertheless some oligonucleotides have been demonstrated to act as anti-cancer agents by an anti-sense mechanism, and one particular anti-sense oligonucleotide is understood to be in clinical trial in the United States.
The art pertaining to the synthesis of chemotherapeutic agents against cancer is even older than the art pertaining to the chemistry and molecular biology of nucleic acids and their components. Whereas numerous cancer chemotherapeutic agents have been developed in the art, have been described in the scientific literature and have been patented, and whereas several are currently used for treatment of cancer in humans, much remains to be desired in this field in terms of efficacy, and selective cytotoxicity to cancer cells. There are also many types of cancers which are more-or-less unaffected by currently available chemotherapeutic agents. There are also cancer cells which although originally vulnerable to certain chemotherapeutic agents, develop resistance to them. There are known cancer cell lines having resistance to multiple drugs (multiple drug resistance, MDR). As far as the present inventors are aware, the present invention provides, for the first time, modified oligonucleotidic compounds which show anticancer activity in other than an "anti-sense" manner, and which show selective toxicity toward certain cancer cell lines, and to certain cancer cell lines with multiple drug resistance.